The present invention provides novel compounds and a novel method for the treatment of Inflammatory Bowel Disease (IBD) with certain azobenzene compounds. In particular it provides 5,5'-azobis-salicylic acid, a compound of formula I of Chart A, and its pharmacologically acceptable salts, which are reductively cleaved to 5-amino salicylic acid by the action of bacteria in the large intestine, and a method of treating or preventing IBD using said compounds.
In addition, it provides novel compounds of formula V of Chart A, the divalent alkali earth metal salts of 5,5'-azobis-salicylic acid. In addition, it further provides the novel trivalent aluminum salt of 5,5'-azobis-salicylic acid, formula VI of Chart A.
IBD is a chronic, nonspecific, inflammatory and ulcerative disease of the colon, and may be characterized by bloody diarrhea. An example is ulcerative colitis. In ulcerative colitis the disease begins in the rectosigmoid area and may extend proximally, eventually involving the entire colon, or it may involve the large bowel at once. See Cecil, Textbook of Medicine, 1568-1578.
Treatment of IBD has been accomplished by several pharmacological routes. Notably, adrenocorticosteroids, belladonna alkaloids, belladonna derivatives, bismuth subcarbonate, kaolin and sulfasalzine are in current use. The adrenocorticosteroids may mask symptoms of intestine perforation and peritonitis and are generally only used for short term therapy, (Goodman & Gilman 4th Ed. pg. 1634 (1970)) and Major complications may occur despite corticosteroid therapy. The belladonna alkaloids and derivatives are largely considered ineffective in IBD. (Goodman & Gilman 4th Ed. pg. 544 (1970). Bismuth subcarbonate is a mechanical protectant and merely prevents further irritation of the condition without any direct effect on the condition. Kaolin is an absorbent which absorbs bacteria and toxins in the colon, but it is doubtful that appreciable activity is retained by the time it reaches the lower bowel. (Goodman and Gilman 4th ed. pg. 990 (1970). Sulfasalazine (SS) is the drug of choice currently for IBD. Its structure is shown in formula II of Chart A. SS is a pro-drug, that is, upon administration, biological processes act upon SS to produce the drug which has the desired biological activity. Upon oral administration, about one-third of a given dose of SS is absorbed from the small intestine. The remaining two-thirds are split by azo-reductase from bacterial flora into sulphapyridine (SP), formula III of Chart A, and 5-aminosalicylic acid (5-ASA) formula IV of Chart A. (Physican's Desk Reference 31st ed. pg. 1250 (1977) See also Klotz, New Eng J. of Med 303, 1499 (1980). It has been determined that the activity of SS comes from the 5-ASA produced. SS is effective as a pro-drug because its relative insolubility prevents its complete absorption in the small intestine thus allowing delivery of SS to the site of administration, i.e., the large intestine. Given separately, both SP and 5-ASA are almost completely absorbed from the small intestine. While effective, SS has several severe side effects including blood dyscrasias and hypersensitivety reactions. This toxicity of SS is due almost entirely to the SP produced.